Title: Crotonaldehyde-induced vascular relaxation and toxicity: Role of endothelium and transient receptor potential ankyrin-1 (TRPA1).

Authors: Jin, L; Jagatheesan, G; Lynch, J; Guo, L; Conklin, D J

Published In Toxicol Appl Pharmacol, (2020 Jul 01)

Abstract: INTRODUCTION: Crotonaldehyde (CR) is an electrophilic α,β-unsaturated aldehyde present in foods and beverages and is a minor metabolite of 1,3-butadiene. CR is a product of incomplete combustion, and is at high levels in smoke of cigarettes and structural fires. Exposure to CR has been linked to cardiopulmonary toxicity and cardiovascular disease. OBJECTIVE: The purpose of this study was to examine the direct effects of CR in murine blood vessels (aorta and superior mesenteric artery, SMA) using an in vitro system. METHODS AND RESULTS: CR induced concentration-dependent (1-300 μM) relaxations (75-80%) in phenylephrine (PE) precontracted aorta and SMA. Because the SMA was 20× more sensitive to CR than aorta (SMA EC50 3.8 ± 0.5 μM; aorta EC50 76.0 ± 2.0 μM), mechanisms of CR relaxation were studied in SMA. The CR-induced relaxation at low concentrations (1-30 μM) was inhibited by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); 4) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); and, 5) by non-vasoactive level of nicotine (1 μM). Similarly, a TRPA1 agonist, allyl isothiocyanate (AITC; mustard oil), stimulated SMA relaxation dependent on TRPA1, endothelium, NO, and GC. Consistent with these mechanisms, TRPA1 was present in the SMA endothelium. CR, at higher concentrations (100-300 μM), induced tension oscillations (spasms) and irreversibly impaired contractility (a vasotoxic effect enhanced by impaired endothelium). CONCLUSIONS: CR relaxation depends on a functional endothelium and TRPA1, whereas vasotoxicity is enhanced by endothelium dysfunction. Thus, CR is both vasoactive and vasotoxic along a concentration continuum.

PubMed ID: 32320793

MeSH Terms: Aldehydes/pharmacology*; Animals; Aorta, Thoracic/drug effects*; Aorta, Thoracic/metabolism; Endothelium, Vascular/drug effects*; Endothelium, Vascular/metabolism; Female; Male; Mice; Muscle, Smooth, Vascular/drug effects; Muscle, Smooth, Vascular/metabolism; NG-Nitroarginine Methyl Ester/pharmacology; Nitric Oxide/metabolism; Phenylephrine/metabolism; TRPA1 Cation Channel/metabolism*; Vasodilation/drug effects*